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We report here that ER\u03b1 is bound to the E-cadherin promoter in both the presence and the complete absence of estrogen, suggesting an unexpected role for unliganded ER\u03b1 in E-cadherin transcription. Indeed, our data reveal that activation by unliganded ER\u03b1 and repression by estrogen-activated ER\u03b1 require direct binding to a half-estrogen response element within the E-cadherin promoter and exchange from associated coactivators to corepressors. Therefore, these results suggest a pivotal role for unliganded ER\u03b1 in controlling a fundamental caretaker of the epithelial phenotype in breast cancer cells. Here, we show that ER\u03b1-positive breast cancer T47D cells transduced with the sfRON kinase undergo a full epithelial\u2013mesenchymal conversion and lose E-cadherin and ER\u03b1 expression. Our data show that, although the E-cadherin gene becomes hypermethylated and heterochromatic, kinase inhibitors can restore E-cadherin expression, together with an epithelial morphology in an ER\u03b1-dependent fashion. Similarly, transfection of ER\u03b1, in the absence of ligands, was sufficient to restore E-cadherin transcription in both sfRON-T47D and other ER\u03b1-, E-cadherin-negative cells. Therefore, our results suggest a novel role for the ER\u03b1 that plays the dual role of ligand-independent activator and ligand-dependent repressor of E-cadherin in breast cancer cells.<\/jats:p>","DOI":"10.1073\/pnas.0903033106","type":"journal-article","created":{"date-parts":[[2009,4,21]],"date-time":"2009-04-21T22:34:59Z","timestamp":1240353299000},"page":"7420-7425","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":38,"title":["ER\u03b1 as ligand-independent activator of CDH-1 regulates determination and maintenance of epithelial morphology in breast cancer cells"],"prefix":"10.1073","volume":"106","author":[{"given":"Maria Dafne","family":"Cardamone","sequence":"first","affiliation":[{"name":"Department of Medicine, Howard Hughes Medical Institute, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651;"},{"name":"Department of Oncological Sciences and"},{"name":"Center for Complex Systems in Molecular Biology and Medicine, University of Torino, 10123 Turin, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Bardella","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences and"},{"name":"Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Turin, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantxa","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Center for Genomic Regulation, Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, c\/ Dr. Aiguader 88, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Di Croce","sequence":"additional","affiliation":[{"name":"Center for Genomic Regulation, Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats, c\/ Dr. Aiguader 88, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Medicine, Howard Hughes Medical Institute, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Flavia","family":"Di Renzo","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences and"},{"name":"Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Torino School of Medicine, 10060 Candiolo, Turin, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"De Bortoli","sequence":"additional","affiliation":[{"name":"Department of Oncological Sciences and"},{"name":"Center for Complex Systems in Molecular Biology and Medicine, University of Torino, 10123 Turin, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,5,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/35021093"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.191367098"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1732912100"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2124"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2005.08.001"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1835"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208991"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.7.3647"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.1.595"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2131"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602996"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1245\/ASO.2005.04.010"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20946"},{"key":"e_1_3_3_14_2","first-page":"5203","article-title":"Estrogen-mediated down-regulation of E-cadherin in breast cancer cells","volume":"63","author":"Oesterreich S","year":"2003","unstructured":"S Oesterreich, et al., Estrogen-mediated down-regulation of E-cadherin in breast cancer cells. 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